Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device

ABSTRACT

A drug-delivery system is provided including at least 100 μg of everolimus and clobetasol, such that the ratio of everolimus to clobetasol is at least 10:1 (w/w) or the amount of everolimus by weight is at least 10 times more than clobetasol. The system can be a stent. Also provided a method of treating restenosis or vulnerable plaque of a blood vessel, the method includes locally administering to a patient a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(N1-tetrazolyl)rapamycin, and locally administering to a patient a second drug consisting of clobetasol, wherein the minimum amount of the first drug that is locally administered is 100 μg, and wherein the ratio of the first drug to the second drug is, for example, 10:1 to 100:1 (w/w).

CROSS-REFERENCE

This is a continuation-in-part of application Ser. No. 11/090,507, filedon Mar. 24, 2005 now U.S. Pat. No. 7,758,881. This is also acontinuation-in-part of application Ser. No. 11/322,282, filed on Dec.29, 2005, which is a continuation of application Ser. No. 10/882,506,filed on Jun. 30, 2004, and is a continuation-in-part of applicationSer. No. 11/089,763, filed on Mar. 25, 2005, now abandoned which is acontinuation-in-part of application Ser. No. 10/320,935, filed on Dec.16, 2002 (U.S. Pat. No. 6,908,624). The specification, disclosure andfigures of all of these references are incorporated herewith in theirentirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a drug combination including ananti-proliferative drug such as everolimus and an anti-inflammatoryagent such as clobetasol for the treatment of a disorder such asrestenosis and vulnerable plaque.

2. Description of the Background

Plaques have been associated with stenosis and restenosis. Whiletreatments of plaque-induced stenosis and restenosis have advancedsignificantly over the last few decades, the morbidity and mortalityassociated with vascular plaques have remained significant. Recent worksuggests that plaque may generally fall into one of two differentgeneral types: standard stenotic plaques and vulnerable plaques.Stenotic plaque, which is sometimes referred to as thrombosis-resistantplaque, can generally be treated effectively by the known intravascularlumen opening techniques. Although plaques induce stenoses, theseatherosclerotic plaques themselves are often benign and are aneffectively treatable disease.

Unfortunately, as plaque matures, narrowing of a blood vessel by aproliferation of smooth muscle cells, matrix synthesis, and lipidaccumulation may result in formation of a plaque which is quitedifferent than a standard stenotic plaque. Such atherosclerotic plaquebecomes thrombosis-prone, and can be highly dangerous. Thisthrombosis-prone or vulnerable plaque may be a frequent cause of acutecoronary syndrome.

While the known procedures for treating plaque have gained wideacceptance and have shown good efficacy for treatment of standardstenotic plaques, they may be ineffective (and possibly dangerous) whenthrombotic conditions are superimposed on atherosclerotic plaques.Specifically, mechanical stresses caused by primary treatments likepercutaneous transluminal intervention (PTI), such as stenting, mayactually trigger release of fluids and/or solids from a vulnerableplaque into the blood stream, thereby potentially causing a coronarythrombotic occlusion. For example, rupture of the fibrous cap thatoverlies the thrombogenic necrotic core is presently believed to play animportant role in acute ischemic events, such as stroke, transientischemic attack, myocardial infarction, and unstable angina (Virmani R,et al. Arterioscler Thromb Vasc Biol. 20: 1262-1275 (2000)). There isevidence that fibrous cap can be ruptured during stent deployment. Humandata from various sources have indicated that lipid rich and/orpositively remodeled and/or echolucent lesions in sysmptomatic coronaryatherosclerosis have higher likelihood for restenosis (See, for example,J. Am. Coll. Cardiol. 21(2):298-307 (1993); Am. J. Cardiol. 89(5):505(2002); Circ. 94(12):3098-102 (1996)). Therefore, there is a need forthe treatment of vulnerable plaques and restenosis.

Furthermore, it may be desirable for PTI treatments to employbiodegradable implantable medical devices. In many treatmentapplications, the presence of a stent in a body may be necessary for alimited period of time until its intended function of, for example,maintaining vascular patency and/or drug delivery is accomplished.Therefore, stents fabricated from biodegradable, bioabsorbable, and/orbioerodable materials such as bioabsorbable polymers should beconfigured to completely erode only after the clinical need for them hasended.

However, one of the major clinical challenges of bioabsorbable stents isadequately suppressing acute or chronic inflammatory responses triggeredby the degradation of the stent. The vascular response to a fullybioabsorbable stent can be much different than that of a metal orpolymer coated stent. Anti-proliferative drugs are often sufficient toreduce neointimal formation, but do not have the ability to adequatelysuppress inflammation. This is reflected by the large number ofgranulomas often seen in chronic porcine studies with drug elutingstents.

The embodiments of the present invention address these and other needs.

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention a drug-delivery device,system or platform is provided, comprising at least 100 μg of everolimusand clobetasol, such that the ratio of everolimus to clobetasol is atleast 10:1 (w/w) or the amount of everolimus by weight is at least 10times more than clobetasol. In one embodiment the system is a stent. Forexample, the system can be a polymeric coated stent, such that theeverolimus and clobetasol are in the polymeric coating. The coating caninclude 2 layers or regions such that the everolimus is in one layer orregion and the clobetasol is in another layer or region. The drugs canbe released in sequence, simultaneously or a combination of both. Forexample the drug release profile can include at least a period ofoverlapping or simultaneous release profile of the everolimus andclobetasol. The ratio of the everolimus to the clobetasol can be 10:1 to100:1 (w/w).

In accordance with another aspect of the invention a stent is provided,comprising a radially expandable body and a combination of (a) a firstdrug selected from a group consisting of rapamycin (sirolimus), BiolimusA9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus,zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus),40-O-(3-hydroxy)propylrapamycin,40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and40-epi-(N-1-tetrazolyl)rapamycin, and (b) a second drug consisting ofclobetasol, carried by the stent, wherein the minimum amount of thefirst drug carried by the stent is 100 μg, and wherein the ratio of thefirst drug to the second drug is 10:1 to 100:1 (w/w). The stent caninclude a coating carrying the first and second drugs. The coating caninclude at least two layers such that the first drug is in one layer andthe second drug is in another layer. The stent can be polymeric,metallic or combination of both. In some embodiments at least one of thedrugs is in the body of the stent and at least one of the drugs is in acoating disposed over the surface of the stent.

In accordance with another aspect of the invention a method of treatingrestenosis or vulnerable plaque of a blood vessel is provided,comprising locally administering to a patient a first drug selected froma group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus,AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578),40-O-(2-hydroxy)ethylrapamycin (everolimus),40-O-(3-hydroxy)propylrapamycin,40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and40-epi-(N1-tetrazolyl)rapamycin, and locally administering to thepatient a second drug consisting of clobetasol, wherein the minimumamount of the first drug that is locally administered is 100 μg, andwherein the ratio of the first drug to the second drug is at least 10:1(w/w). The ratio of the first drug to the second drug can be 10:1 to100:1 (w/w). In some embodiments, local administration is by a stentsuch as a polymer coated stent or a bioabsorbable stent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts an illustration of a stent.

FIG. 2 depicts an illustration of a section of a stent.

FIGS. 3A-B depict cross-sections of a strut illustrating geometries ofdepots.

FIGS. 4A-B depicts cross-sections of a strut with a coating.

FIG. 5 shows the results of 28 day quantitative coronary angioplasty(QCA) of a porcine implant study on drug-delivery systems describedherein.

FIG. 6 shows 28 day histology data of a porcine implant study ondrug-delivery systems described herein.

FIG. 7 shows the 28 day morphometry data of a porcine implant study ondrug-delivery systems described herein.

FIG. 8 shows the results of 28 day quantitative coronary angioplasty(QCA) of a porcine implant study on drug-delivery systems describedherein.

FIG. 9 depicts a proliferation assay that shows a dose dependentinhibition of vascular smooth muscle proliferation.

FIG. 10 depicts a proliferation assay with everolimus which also showsinhibition of vascular smooth muscle proliferation.

FIG. 11 depicts results of a proliferation assay with varying ratios ofeverolimus and clobetasol.

DETAILED DESCRIPTION Anti-Proliferative Agents and Anti-InflammatoryAgents

In accordance with one embodiment, described herein are drug-deliverysystems, devices or platforms and methods of using the drug-deliverysystems, devices or platforms for the treatment of a vascular disorder.The term “treatment” includes prevention, reduction, delay orelimination of the vascular disorder. In some embodiments, treatmentalso includes repairing damage caused by the disorder and/or themechanical intervention (e.g., stenting, balloon dilation, etc.). Thedrug-delivery system has two or more drugs for treating a vasculardisorder or a related disorder. The drugs can be a combination of atleast one anti-proliferative agent, at least one anti-inflammatoryagent, and optionally a third bioactive agent. In one embodiment, thedrug-delivery system consists only of two drugs, an anti-proliferativeagent and an anti-inflammatory agent. In one embodiment, the drugs caninclude or only consist of everolimus and clobetasol. Everolimus isavailable under the trade name Certican™, Novartis Pharma AG, Germanyand clobetasol is available under the trade name Temovate™,Glaxosmithkline, UK. The amount of the anti-proliferative agent oreverolimus included or carried by the system can be at least 100 μg andthe ratio of the anti-proliferative agent or everolimus to theanti-inflammatory agent or clobetasol can be at least 10:1 (w/w). In onepreferred embodiment, the ratio is 10:1 to 100:1 (w/w).

In a preferred embodiment, the system includes a first drug selectedfrom a group consisting of rapamycin (sirolimus), Biolimus A9,deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus,zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus),40-O-(3-hydroxy)propylrapamycin,40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and40-epi-(N1-tetrazolyl)rapamycin, and a second drug consisting ofclobetasol. The minimum amount of the first drug carried by the system(e.g., stent) is 100 μg and the ratio of the first drug to the seconddrug is 10:1 to 100:1 (w/w). In one preferred embodiment, the systemconsists solely of the first and second drug combination with no otherdrugs present.

In one embodiment, a medical composition, such as in a liquid carrier,is described including an effective amount of at least oneanti-inflammatory agent and an effective amount of an anti-proliferativeagent. In another embodiment, the composition described herein includesan effective amount of an agent which is effective both as ananti-inflammatory agent and as an anti-proliferative agent. Thecomposition can, for example, be administered orally, intravenously, orformed into a coating for an implantable medical device such as a stentor a balloon of a catheter. The anti-proliferative agent can beeverolimus or others described herein, and the anti-inflammatory agentcan be clobetasol.

The anti-proliferative agent and the anti-inflammatory agent can be inthe form of a coating with or without a polymer matrix on a medicaldevice (e.g., stent) or at least one of the agents can be administeredin a separate dose form such as bolus dose of a free drug, optionallywith fluoroscopic dye, or bolus dose of a gel encapsulating the drug.The drug-delivery system or composition may further include a thirdagent such as a high-density lipoproptein mimetic (HDL-mimetic). Forexample, an anti-inflammatory agent such as clobetasol can be deliveredalong with the catheter based delivery of a HDL-mimetic while everolimusis administered by a stent.

The drug-delivery system or composition disclosed herein can be used totreat a disorder such as thrombosis, high cholesterol, hemorrhage,vascular dissection or perforation, vascular aneurysm, vulnerableplaque, chronic total occlusion, claudication, anastomotic proliferationfor vein and artificial grafts, bile duct obstruction, ureterobstruction, tumor obstruction, restenosis and progression ofatherosclerosis in patient subsets including type I diabetics, type IIdiabetics, metabolic syndrome and syndrome X, vulnerable lesionsincluding those with thin-capped fibroatheromatous lesions, systemicinfections including gingivitis, hellobacteria, and cytomegalovirus, andcombinations thereof.

Inflammation in Stenting a Vessel

A common disorder in association with mechanical modification of avessel, such as by a balloon or stenting is restenosis. A number ofcellular mechanisms have been proposed that lead to restenosis of avessel. Two of these mechanisms are (1) the migration and proliferationof smooth muscle cells to and at the site of injury, and (2) the acuteand chronic inflammatory response to injury and foreign body presence.

Inflammation is a defensive, biological response to injury, infection oran abrupt change in tissue homeostasis. Inflammation can occur anywherein the body, and most of the time is confined to that part of the body.Well-known indicators of inflammation are pain, redness, warmth,swelling, and loss of function. In nature, inflammatory responses aredesigned to destroy, dilute and isolate injurious agents and then leadto recovery and repair of the affected tissue. The intensity of aninflammatory response can vary from one that is self-limiting, whichrequires minor therapeutic intervention, to one that is lifethreatening, which requires intense intervention. One drawback of theinflammatory process is its ability to become progressive, meaningtissue damage continues after the stimulus is neutralized or removed.

Vascular inflammation is the first stage of the inflammatory response,developing after the initial contact with the stimulus and continuingsometimes for several days. The presence of a stimulatory agent in theblood or in the tissue triggers the body's response through endothelialcells. The endothelial cell layer is the innermost layer of largervessels and the only cell layer of the smallest vessels, thecapillaries. Endothelial cells produce substances called chemokines thatattract neutrophils and other white blood cells to the site of injury.Within the site, neutrophils and endothelium relay information back andforth across cell membranes through presentation of adhesion moleculesand cytokines. Cellular cross-talk promotes physical interaction betweenthe “inflamed” neutrophil and the “inflamed” endothelium.

Additionally, the presence of a biodegradable foreign body, such as abiodegradable implantable medical device (e.g., a stent), in a vesselcan lead to or aggravate an inflammatory response, thus leading to amore aggressive restenotic process. Biodegradation refers generally tochanges in physical and chemical properties that occur (e.g., in apolymer) upon exposure to bodily fluids as in a vascular environment.The changes in properties may include a decrease in molecular weight,deterioration of mechanical properties, and decrease in mass due toerosion or absorption. The decrease in molecular weight may be caused bychemical reactions of bodily fluids with the polymer, for example,hydrolysis and/or metabolic processes. By-products of such degradationreactions can be responsible for inciting inflammation. For example,by-products of hydrolysis are produced when polymer molecules arecleaved into component parts by the addition of water. Variousbyproducts of degradation of biodegradable polymers are known to incitean inflammatory response. For example, lactic acid, a degradationby-product of poly(lactic acid) polymers, is known to cause aninflammatory response.

Furthermore, the release of by-products into the body from abiodegradable device occurs continuously from the time of first exposureto bodily fluids to a time when the device is either completely degradedand eliminated or removed from the body. It follows that throughout thistime frame, the body is continuously exposed to inflammation-incitingby-products. Therefore, in some embodiments, it is desirable to have asustained release of an anti-inflammatory agent from a degradingimplanted device throughout this time frame.

Another important pathological feature of vascular inflammation isendothelial cell swelling. This action reduces the functional vesseldiameter such that the speed of blood flow falls significantly and thevessel becomes congested. When these conditions predominate, inflamedneutrophils are induced to plug the vessel. As a result, endothelialcells lose their tight connections allowing neutrophils to transmigrateinto the surrounding tissue.

Within hours of the initial stimulus, neutrophils begin to enter thetissue and may continue transmigration for many days. The appearance ofinflammatory cells in the surrounding tissue marks the beginning oftissue damage. In some inflammatory conditions, tissue damage is causedby direct injury of the vessels and amplified by the subsequentrecruitment of neutrophils into the tissue.

Activated by local mediators, neutrophils and tissue macrophages aretriggered to release agents that destroy toxins and clean up dead cellsin the area. Unfortunately, these same agents also cause collateraldamage to healthy cells, which further extends the borders of theinitial tissue destruction.

Tissue repair is the third and final stage of inflammation. It may takeseveral days for tissue destruction to reach full intensity beforetapering off. Until then, the tissue repair process that consists ofgrowth of new blood vessels and entry of monocytes to clean up thedebris is delayed. Fibroblasts also enter the local tissue to replacethe extracellular matrix and collagen. The process of tissue repair isstringently controlled within the tissue site. If the process becomesdysregulated, inappropriate tissue repair will lead to excessivescarring. Depending on the tissue and the intensity/duration of theinflammatory condition, the amount of scarring can be significant.

An example of disorders that vessel inflammation is involved isvulnerable plaque (VP) rupture. Previous studies have demonstrated thatinflammation promotes proliferation at sites of balloon angioplasty andstent placement in pigs (Kornowski, et al., Coron Artery Dis.12(6):513-5 (2001)). Since sites of vulnerable plaque have a higherdensity of macrophages and lymphocytes than other types ofatherosclerotic lesions, it is expected that these sites, when stented,will produce elevated amounts of the cytokines (IL-1, TNF-alpha) thatpromote smooth muscle cell proliferation.

Another example of disorders that vessel inflammation is involved isdiabetes. Studies have shown that patients with type-2 diabetes havehigher rates of restenosis than the general population. The diabeticpatient is in pro-inflammatory state that can amplify restenosis becausediabetic lesions contain a large number of inflammatory cells (e.g.,macrophages, lymphocytes, etc.).

Implantable Medical Devices

The system, device or platform of the present invention can be a medicaldevice, preferably an implantable medical device. The term “implantablemedical device” is intended to include self-expandable stents,balloon-expandable stents, stent-grafts, and grafts. An implantablemedical device also includes a body structure, substrate, or scaffoldingfor medical use that can be permanently or temporarily implanted in asubject. The structure of the device can be of virtually any design. Astent, for example, may include a pattern or network of interconnectingstructural elements or struts. FIG. 1 depicts an example of athree-dimensional view of a stent 10. The stent may have a pattern thatincludes a number of interconnecting elements or struts 15. Theembodiments disclosed herein are not limited to stents or to the stentpattern illustrated in FIG. 1. For example, the cross-section of a strutmay be rectangular, (as pictured in FIG. 1), circular, oval, etc.

The struts of the stent in FIG. 1 may further be described as havingabluminal (outer) faces 20, luminal (inner) faces 25, and sidewalls 30.The embodiments are easily applicable to other patterns and otherdevices. In general, the variations in the structure of patterns arevirtually unlimited. As shown in FIG. 1 the geometry or shape of stentsvary throughout its structure.

In some embodiments, a stent may be formed from a tube by laser cuttingthe pattern of struts into the tube. The stent may also be formed bylaser cutting a polymeric or metallic sheet, rolling the pattern intothe shape of the cylindrical stent, and providing a longitudinal weld toform the stent. Other methods of forming stents are well known andinclude chemically etching a sheet and rolling and then welding it toform the stent. A polymeric or metallic wire may also be coiled to formthe stent. The stent may be formed by injection molding of athermoplastic or reaction injection molding of a thermoset polymericmaterial. Filaments of the compounded polymer may be extruded or meltspun. These filaments can then be cut, formed into ring elements, weldedclosed, corrugated to form crowns, and then the crowns welded togetherby heat or solvent to form the stent. Lastly, hoops or rings may be cutfrom tubing stock, the tube elements stamped to form crowns, and thecrowns connected by welding or laser fusion to form the stent.

The underlying structure or substrate of an implantable medical device,such as a stent can be completely or at least in part be made from abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers.

Additionally, a polymer-based coating for a surface of a device can be abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers. The coating can include anynumber of layer or regions such as primer layer, reservoir layerincluding the drugs, multiple reservoir layers each including a drug,top coat layer or any combination of these layers. In one embodiment,both the anti-proliferative and anti-inflammatory agent are included ormixed in a single reservoir layer of polymer(s). In another embodiment,a bottom reservoir layer can include the anti-proliferative and the topreservoir layer can include the anti-inflammatory agent.

Examples of other implantable devices include artificial heart valves,cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads.

The device (e.g., stent) can be made of a metallic material or an alloysuch as, but not limited to, cobalt chromium alloy (ELGILOY), stainlesssteel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobaltchrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE (Nitinol), tantalum,nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, orcombinations thereof. “MP35N” and “MP20N” are trade names for alloys ofcobalt, nickel, chromium and molybdenum available from Standard PressSteel Co., Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel,20% chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention. In one embodiment, the implantabledevice is a stent, which can be degradable stents, biodurable stents,depot stents, and metallic stents such as stents made of stainless steelor nitinol.

Anti-Proliferative Agents

Any drugs having anti-proliferative effects can be used in the presentinvention. The anti-proliferative agent can be a natural proteineousagent such as a cytotoxin or a synthetic molecule. The active agentsinclude anti-proliferative substances such as actinomycin D, orderivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN available fromMerck) (synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁), all taxoids such astaxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimusdrugs such as macrolide antibiotics, rapamycin, everolimus, structuralderivatives and functional analogues of rapamycin, structuralderivatives and functional analogues of everolimus, FKBP-12 mediatedmTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugsthereof, and combinations thereof. Preferably the drug is rapamycin(sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus,temsirolimus, pimecrolimus, zotarolimus (ABT-578),40-O-(2-hydroxy)ethylrapamycin (everolimus),40-O-(3-hydroxy)propylrapamycin,40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, and 40-O-tetrazolylrapamycinand 40-epi-(N1-tetrazolyl)rapamycin, prodrugs thereof, co-drugs thereof,and combinations thereof.

In one embodiment, the anti-proliferative agent is everolimus.Everolimus acts by first binding to FKBP12 to form a complex (Neuhhaus,P., et al., Liver Transpl. 2001 7(6):473-84 (2001) (Review)). Theeverolimus/FKBP12 complex then binds to mTOR and blocks its activity(Id.). By blocking mTOR activity, cells are unable to pass through G1 ofthe cell cycle and as a result, proliferation is inhibited. mTORinhibition has also been shown to inhibit vascular smooth musclemigration.

Anti-inflammatory Agents

Any drugs having anti-inflammatory effects can be used in the presentinvention. The anti-inflammatory drug can be a steroidalanti-inflammatory agent, a nonsteroidal anti-inflammatory agent, or acombination thereof. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, deflazacort, desonide, desoximetasone, dexamethasonedipropionate, diclofenac potassium, diclofenac sodium, diflorasonediacetate, diflumidone sodium, diflunisal, difluprednate, diftalone,dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium,epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen,fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone,fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin,flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugsthereof, and combinations thereof.

In one embodiment, the anti-inflammatory agent is clobetasol. Clobetasolis a corticosteroid that binds to corticosteroid receptors, a class ofnuclear receptor. The binding of clobetasol to the corticosteroidreceptor subsequently alters gene expression in such a way thatinflammation is inhibited. For example, corticosteroids inhibit theactivation of NFkB, the nuclear factor that is responsible for changesin gene expression that promote inflammation. The reduction ininflammation may also inhibit the mechanisms that promote small musclecell (SMC) hyper proliferation. This is shown in that dexamethasone, aless potent glucocorticoid as compared to clobetasol, reduces theproduction of PGDF and thus has anti-proliferative properties.Clobetasol acts through similar pathways and is more potent thandexamethasone.

Dosage

The dosage or concentration of the anti-proliferative andanti-inflammatory agents required to produce a favorable therapeuticeffect should be less than the level at which the bioactive agentproduces toxic effects and greater than the level at whichnon-therapeutic results are obtained. The dosage or concentration of theagents required can depend upon factors such as the particularcircumstances of the patient, the nature of the trauma, the nature ofthe therapy desired, the time over which the ingredient administeredresides at the vascular site, and if other active agents are employed,the nature and type of the substance or combination of substances.Therapeutic effective dosages can be determined empirically, for exampleby infusing vessels from suitable animal model systems and usingimmunohistochemical, fluorescent or electron microscopy methods todetect the agent and its effects, or by conducting suitable in vitrostudies.

In one embodiment, the bioactive agents can be incorporated intopolymeric coating (e.g., of the stent) in a percent loading of betweenabout 0.01% and less than about 100% by weight, more preferably betweenabout 5% and about 50% by weight of the total drug-load that includesgreater than about 0% to about 100% of the anti-proliferative agent andless than about 100% to greater than about 0% of the anti-inflammatoryagent. The relative amount of the anti-proliferative agent andanti-inflammatory agent can be determined by the type of lesions to betreated. For example, where everolimus is used as the anti-proliferativeagent and clobetasol is used as the anti-inflammatory agent, therelative amount of everolimus and clobetasol can be varied for differenttypes of lesions, that is, the relative amount of everolimus can behigher for more proliferative lesions, and on the other hand, therelative amount of clobetasol can be higher for more inflammatorylesions.

Preferably the amount of everolimus (or the other listedanti-proliferative agents) carried by the stent is not less than 100 μgand the ratio of everolimus (or the other listed anti-proliferativeagents) to clobetasol (or the other listed anti-inflammatory agents) isat least 10:1 (w/w). In one embodiment the ratio is 10:1 to 100:1 (w/w).

Other Bioactive Agents

In some embodiments, other agents can be used in combination with theanti-proliferative agent and the anti-inflammatory agent. Thesebioactive agents can be any agent which is a therapeutic, prophylactic,or diagnostic agent. These agents can also have anti-proliferativeand/or anti-inflammatory properties or can have other properties such asantineoplastic, antiplatelet, anti-coagulant, anti-fibrin,antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant aswell as cystostatic agents. Examples of suitable therapeutic andprophylactic agents include synthetic inorganic and organic compounds,proteins and peptides, polysaccharides and other sugars, lipids, and DNAand RNA nucleic acid sequences having therapeutic, prophylactic ordiagnostic activities. Nucleic acid sequences include genes, antisensemolecules which bind to complementary DNA to inhibit transcription, andribozymes. Some other examples of other bioactive agents includeantibodies, receptor ligands, enzymes, adhesion peptides, blood clottingfactors, inhibitors or clot dissolving agents such as streptokinase andtissue plasminogen activator, antigens for immunization, hormones andgrowth factors, oligonucleotides such as antisense oligonucleotides andribozymes and retroviral vectors for use in gene therapy. Examples ofantineoplastics and/or antimitotics include methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorssuch as Angiomax ä (Biogen, Inc., Cambridge, Mass.), calcium channelblockers (such as nifedipine), colchicine, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO), estradiol,anticancer agents, dietary supplements such as various vitamins, and acombination thereof. Examples of such cytostatic substance includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford,Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® fromMerck & Co., Inc., Whitehouse Station, N.J.). An example of anantiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate include alpha-interferon,and genetically engineered epithelial cells. The foregoing substancesare listed by way of example and are not meant to be limiting. Otheractive agents which are currently available or that may be developed inthe future are equally applicable.

Delivery Formulations

The composition comprising both anti-proliferative agent and theanti-inflammatory agent can be formulated into any formulation suitablefor delivery by any mode of delivery. For example, the composition canbe formed into a coating on an implantable medical device to providecontrolled release of the anti-proliferative agent and theanti-inflammatory agent. Preferably, they are included in a polymericcoating on a stent. The composition can also be formulated into othersuitable formulations for example, bolus dose of free drug, optionallywith a fluoroscopic dye, bolus dose of gel-encapsulated drug.

The gel can be formed of a gel-forming material or polymer such ashyaluronic acid, carboxymethyl cellulose, pectin, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, sodiumcarboxymethylcellulose, hydroxyethylcellulose, polyethylene oxide,acacia, tragacanth, guar gum, xanthan gum, locust bean gum, Carbopol™acidic carboxy polymer, polycarbophil, polyethylene oxide,poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinylacetate) cross-linked with hydrolyzable bonds, water-swellable N-vinyllactams polysaccharides, natural gum, agar, agarose, sodium alginate,carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gumarabic, gum ghatti, gum karaya, arbinoglactan, amylopectin, gelatin,hydrophilic colloids such as carboxylmethyl cellulose gum or alginategum, including both non-crosslinked and crosslinked alginate gums, wherethe crosslinked alginate gums may be crosslinked with di- or trivalentions, polyols such as propylene glycol, or other crosslinking agents,Cyanamer™ polyacrylamides, Good-rite™ polyacrylic acid, starch graftcopolymers, Aqua-Keeps™ acrylate polymer, ester crosslinked polyglucan,and the like, and combinations thereof. Some of the gel-formingmaterials are discussed in U.S. patents, U.S. Pat. Nos. 3,640,741,3,865,108, 3,992,562, 4,002,173, 4,014,335, and 4,207,893. Hydrogelsalso are discussed in the Handbook of Common Polymers, by Scott andRoff, published by the Chemical Rubber Company, Cleveland, Ohio. For anygiven gel-forming material or polymer, use of a material with higheraverage molecular weight provides higher viscosity in aqueous solutionof any given concentration. Therefore, using a higher molecular weightgenerally enables use of a lesser quantity of polymer to accomplish therequired retardation of dissolution. In some embodiments, thegel-forming material or polymer can be hydropropyl methylcellulosehaving 19-24% methoxyl substitution and 7-12% hydroxypropyl substitutionand a number average molecular weight of at least 20,000. Such polymersinclude those sold by Dow Chemical Co. under the tradenames MethocelK4M, Methocel K15M and Methocel K100M.

Modes of Delivery

In one embodiment, the anti-inflammatory drug such as clobetasol isformulated into a bolus dose of free drug with, optionally, afluoroscopic dye. The anti-proliferative drug such as everolimus can beformulated into a coating composition with a polymeric material and thencoated onto an implantable device (e.g., stent). The bolus dose ofanti-inflammatory drug is administered first and then theanti-proliferative drug is delivered by release from the implantabledevice such as a drug-delivery stent. The composition may furtherinclude a third agent such as a HDL (high density lipoprotein)-mimic asdescribed in U.S. Pat. No. 6,367,479. Alternatively, HDL-mimic can bedelivered by the stent.

In another embodiment, the anti-inflammatory drug such as clobetasol isformulated into a bolus dose of gel. The anti-proliferative drug such aseverolimus can be formulated into a coating composition with a polymericmaterial and then coated onto an implantable device. The bolus dose ofthe anti-inflammatory drug is administered first and then theanti-proliferative drug is delivered by release from the implantabledevice such as a drug-delivery stent.

In a further embodiment, the anti-inflammatory drug and theanti-proliferative drug can be included in a polymeric matrix and thencoated onto a medical device such as a stent. The coating can be asingle layer or include multiple layers or regions. One layer or regioncan include the anti-proliferative drug (e.g., everolimus) and anotherlayer or region can include the anti-inflammatory drug (e.g.,clobetasol). The medical device coating can be designed to have avariety of different release parameters for each of the drugs includedin the coating. Methods of coating stents with drug/polymer combinationsare well known in the art.

As indicated above, the release of inflammation-inciting by-productsinto the body from a biodegradable device can occur continuously whilethe device is degrading within the body. Therefore, embodiments of adrug-delivery system having a sustained release of an anti-inflammatoryagent from an implanted device are described.

Certain embodiments of a drug-delivery system may include an effectiveamount of an anti-proliferative agent. The drug delivery system mayfurther include a body structure of an implantable medical device. Insome embodiments, the body structure may be a substrate or scaffoldingof an implantable medical device, such as stent. The substrate orscaffolding may be a biostable or bioabsorbable polymer. An embodimentof the drug-delivery system may further include an effective amount of asteroidal anti-inflammatory agent or a non steroidal anti-inflammatoryagent within the body structure of the device. An anti-inflammatoryagent within a biodegradable body structure may allow for sustainedrelease of the inflammatory agent throughout the degradation process ofthe body structure.

In one embodiment, at least some of the anti-proliferative agent may becontained in a coating on the body structure of the device. The coatingmay be pure or substantially pure agent or mixed or dispersed in abiostable or bioabsorbable polymer matrix. Alternatively, at least someof the anti-proliferative agent may be delivered in some other localmanner or systemically.

An embodiment of a method of treating restenosis or vulnerable plaque ofa blood vessel may include administering to a patient an effectiveamount of an anti-proliferative agent (e.g., everolimus or other listeddrugs) either through a coating on a device, systemically, and/or someother local method. The method may further include allowing an effectiveamount of a steroidal anti-inflammatory agent or a non steroidalanti-inflammatory agent (e.g., clobetasol) to elute to a vessel fromwithin a body structure the device. At least a portion of theanti-inflammatory agent in at least one depot and/or anti-inflammatoryagent mixed or dispersed within the body structure may elute from asurface of the body structure. In some embodiments, theanti-inflammatory agent may elute through a coating containing at leasta portion of the anti-proliferative agent. In one embodiment, at least aportion of the anti-inflammatory agent may elute from the body structureand suppress inflammation of a blood vessel during all or a majority ofthe degradation of the body structure.

Moreover, the properties of the coating, such as thickness and porosity,may influence the rate of release of the anti-inflammatory agent fromthe device. Some embodiments may include controlling the release rate ofanti-proliferative agent by modifying the properties of the coating.

In one embodiment, at least a portion of the anti-inflammatory agentwithin the body structure may be contained in at least one depot orcavity on at least a portion of a surface of the body structure. Theagent in the depot may be pure or substantially pure agent.Alternatively, the agent in the depot may be mixed or dispersed in apolymer matrix.

Numerous embodiments of implantable medical devices with depotsconfigured to hold an agent are possible. Depots may be placed at one ormore arbitrary locations on a device. In some embodiments, depots may beselectively distributed at or near portions of a device that areadjacent to regions of a vessel in need of treatment for inflammation.For example, in long lesions, the center portion of the lesion may bemore inflamed than the ends of the lesion. The greater inflammation mayarise from a larger concentration of degradation products closer to thecenter of the stent than the ends of the stent. Thus, the center of thelesion may require more anti-inflammatory agent than the ends of thelesion. Alternatively, the ends of the lesion may be more inflamed dueto mechanical stresses causing irritation or injury to the ends of thelesion. Thus, a stent may include depots or more depots in regions of astent adjacent portions of a lesion having more inflammation.

Additionally, depots may be selectively disposed on abluminal faces,luminal faces, and/or sidewalls of a stent. For example it may bedesirable to have depots on abluminal faces since they may be in contactwith inflamed portions of a vessel. However, depots may be placed at anylocation on a stent that could be clinically beneficial in treatingrestinosis. FIG. 2 depicts a section 50 of stent 10 from FIG. 1. Insection 50, depots 55 are disposed on an abluminal face 20 and depots 60are disposed on a sidewall 30.

Additionally, the geometrical parameters that characterize depots suchas size (e.g., depth, diameter, etc.) and shape may be configured tofacilitate treatment of an inflammatory response. For example, thegeometry of depots may be configured to maximize sustained delivery ofanti-inflammatory agent throughout the degradation of a device tocounteract the inflammatory effect of degradation by-products.

A single depot or plurality of depots may be formed as a laser trench orlaser trenches on a body of an implantable medical device such as stent10 by exposing a surface of the device to an energy discharge from alaser, such as an excimer laser. Alternative methods of forming depotsinclude, but are not limited to physical or chemical etching techniques.Techniques of laser fabrication or etching to form depots are well-knownto one of ordinary skill in the art. Depots can be formed in virtuallyany stent structure and not merely the above-described structure.

FIGS. 3A-B depict cross-sections of a strut illustrating geometries ofdepots. Referring to FIG. 3A, depot 70 has a generally cylindricalshape. Depot 70 has a depth D₁ and diameter D₂. The appropriate valuesfor D₁ and D₂ depend on factors such as the effective amount of agent,mechanical integrity of the strut, density of depots, and the desiredtime frame of release of active agent. For instance, the greater theeffective amount of agent, the larger either or both depth D₁ anddiameter D₂ may need to be. A higher density of depots disposed on astrut may decrease a required amount of agent in an individual strut,and thus a necessary size of a depot. Furthermore, as the size anddensity of the depots increase, the mechanical strength of the strut maydecrease. Additionally, a longer sustained release of active agent maybe facilitated by a larger depth D₁. A diameter D₂ of cylindrical depot70 may have a range from about 10% to about 95%, about 20% to about 80%,30% to about 70%, or about 40% to about 60% of width W₁.

FIG. 3B illustrates a depot 75 which is generally conical in shape.Conical shaped depot 75 has an open end 80 and a closed end 85. Open end80 is the end that contacts a surface of a tissue since open end 80 isat abluminal face 20. A diameter D₃ of conical shaped depot 75 is shownto decrease from closed end 85 to open end 80. The largest diameter D₃′is at the closed end 85 of conical shaped depot 75. D₃′ may have a rangefrom about 10% to about 95%, about 20% to about 80%, 30% to about 70%,or about 40% to about 60% of width W₁. The smallest diameter D₃″ at openend 80 of conical shaped depot 75 may have a range from about 1% toabout 70%, about 5% to about 70%, about 15% to about 60% of about 30% toabout 50% of width W₁. The reduced size of opening 80 of conical shapeddepot 75, as compared to that of the cylindrical shaped depot 70, mayreduce the rate at which the anti-inflammatory agent is released oncethe stent is implanted at the desired location of treatment. The depotscan have a variety of other geometrical shapes, such as elongatedtrenches (not illustrated).

In other embodiments, at least a portion of the anti-inflammatory agentwithin the body structure may be mixed or dispersed within the bodystructure of the device. The anti-inflammatory agent mixed or dispersedwithin a biodegradable body structure may elute into a vessel atsubstantially the same rate as the body structure degrades. In oneembodiment, the anti-inflammatory agent may be incorporated (mixed ordispersed) within the body structure during fabrication of the device.For example, the agent may be mixed with polymer in a molten statebefore, during, and/or after a fabrication process such as extrusion orinjection molding. However, it is important to control the temperatureof an molten polymer containing agent during a mixing process to inhibitor prevent degradation of the active agent. The temperature of a moltenpolymer may be controlled to be below a degradation temperature ordegradation temperature range. Some agents tend to degrade attemperatures above about 80° C. Others may tend to degrade above about100° C.

FIGS. 4A-B depict cross-sections of struts having anti-inflammatoryagent within that is below a coating 105 and 115. Coating 105 and 115may include an anti-proliferative agent. In FIG. 4A, a composition 100that is pure anti-inflammatory agent or anti-inflammatory agentdispersed within a polymer matrix is deposited within depot 70.Anti-inflammatory agent is configured to elute through coating 105 totreat inflamed portions of vessels. FIG. 4B depicts an anti-inflammatoryagent 110 dispersed within the strut. Anti-inflammatory agent 110 isconfigured to elute through coating 115 to treat inflamed portions ofvessels.

An anti-inflammatory can have one or a combination of release profilesthat include a pulse release, fast or burst release, and a sustainedrelease. Similarly, the anti-proliferative drug can have one or acombination of release profiles that include a pulse release, fast orburst release, and a sustained release from the stent. In someembodiments, the combination can be delivered simultaneously or at leastduring the drug treatment period there is at lease some overlap betweenthe release of the drugs. In some embodiments, the anti-inflammatory canbe completely released prior to the release to the anti-proliferative orcan be partially released with some or significant overlap between therelease of both drugs. “Pulse release” generally refers to a releaseprofile of a drug that features a sudden surge of the release rate ofthe drug. The release rate surge of the drug would then disappear withina period. A more detailed definition of the term can be found inEncyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed.,Culinary and Hospitality Industry Publications Services.

As used herein, the term “fast release” in one embodiment refers to arelease profile of a drug that features a release rate in the rangebetween about 15 to about 40 μg per day for a 18 mm stent, about 10 μgto about 27 μg per day for a 13 mm stent, and about 6.7 μg to about 17.2μg per day for a 8 mm stent. Equivalent profiles can be derived by onehaving ordinary skill in the art for stents having other sizes. Inanother embodiment, the term “fast release” refers to an approximately20% release in 24 hours of a drug. The term “fast release” is usedinterchangeably with the term “burst release.”

As used herein, the term “sustained release” generally refers to arelease profile of a drug that can include zero-order release,exponential decay, step-function release or other release profiles thatcarry over a period of time, for example, ranging from several days toseveral years. The terms “zero-order release”, “exponential decay” and“step-function release” as well as other sustained release profiles arewell known in the art (see, for example, Encyclopedia of Controlled DrugDelivery, Edith Mathiowitz, Ed., Culinary and Hospitality IndustryPublications Services).

In one embodiment, at least one of the anti-inflammatory agent (e.g.,clobetasol) and anti-proliferative agent (e.g., everolimus) isadministered via a stent while the other is administered by other localmeans of administration (e.g., coated balloon or drug delivery balloon)or alternatively, the other is administered systemically. In otherembodiments, both are administered locally, by means other than a stent,or alternatively systemically. Systemic administration can beaccomplished orally or parenterally including intravascularly, rectally,intranasally, intrabronchially, or transdermally. Liquid carriers whichare sterile solutions or suspensions can be injected intramuscularly,intraperitoneally, subcutaneously, and intravenously. Rectaladministration can be in the form of conventional suppository. Foradministration by intranasal or intrabronchial inhalation orinsufflation, the drug can be formulated into an aqueous or partiallyaqueous solution, which can then be utilized in the form of an aerosol.The drug can be administered transdermally through the used of atransdermal patch and a carrier that is inert to and mutually compatiblewith the active component, is non-toxic to the skin, and allows for thedelivery of the drug for systemic absorption into the blood stream viathe skin. The carrier may take any number of forms such as creams,ointments, pastes, and gels. The creams and ointments may be viscousliquids or semisolid emulsions of either the oil-in-water orwater-in-oil type. Pastes made of absorptive powders dispersed inpetroleum or hydrophilic petroleum containing the active component mayalso be suitable. Other devices capable of releasing the drug into theblood stream include semi-permeable membranes covering a reservoircontaining the drug, with or without a carrier.

Local administration can be accomplished by a variety of techniqueswhich administer the active component at or near the target site.Preferably, local administration is by a stent. The following examplesof local delivery techniques are provided for illustrative purposes andare not intended to be limiting. Examples include local deliverycatheters, site specific carriers, particles, implants, directapplication, or direct injection. Local delivery by a catheter allowsfor the administration of the drug directly to the target site.

Local delivery by site specific carriers is conducted by attaching thedrug to a carrier which will direct or link the drug to the targetcells. Examples of this delivery technique include the use of carriersuch as a protein ligand, a monoclonal antibody or a membrane anchoredlinker.

Local delivery by an implant (other than a stent) is the placement of amatrix carrying the drug at the site. The matrix can release the activecomponent by, for example, diffusion, degradation, chemical reaction,solvent activators, etc. One example of local delivery by an implant caninclude direct injection of vesicles or micro-particles. Thesemicro-particles may be composed of substances such as proteins, lipids,carbohydrates or synthetic polymers. The micro-particles can have thedrug impregnated therein and/or coated thereon. Application via implantsis not limited to the above described routes and other techniques suchas grafts, micropumps or application of a fibrin glue or hydrogelcontaining the active component around the exterior of a designatedregion of the vessel can also be implemented by one of ordinary skill inthe art.

Local delivery by direct injection describes injecting a liquid carriercontaining the drug directly into the site. The liquid carrier should beinert to and mutually compatible with the drug. The component can be intrue solution or suspended in fine particles in the carrier. A suitableexample of an inert carrier includes a sterile saline solution.

Biocompatible and Bioabsorbable Polymers

In general, polymers can be biostable, bioabsorbable, biodegradable, orbioerodable. Biostable refers to polymers that are not biodegradable.The terms biodegradable, bioabsorbable, and bioerodable, as well asdegraded, eroded, and absorbed, are used interchangeably and refer topolymers that are capable of being completely eroded or absorbed whenexposed to bodily fluids such as blood and can be gradually resorbed,absorbed and/or eliminated by the body.

Representative examples of polymers that may be used to fabricate animplantable medical device, to coat an implantable medical device, or toprovide a drug delivery particle with the anti-proliferative drug and/oranti-inflammatory drug include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(3-hydroxyvalerate),poly(lactide-co-glycolide), poly(3-hydroxybutyrate),poly(4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate),polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid),poly(D,L-lactide), poly(L-lactide-co-D,L-lactide), poly(caprolactone),poly(L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone),poly(glycolide-co-caprolactone), poly(trimethylene carbonate), polyesteramide, poly(glycolic acid-co-trimethylene carbonate),co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules(such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid), polyurethanes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers other than polyacrylates, vinyl halide polymers andcopolymers (such as polyvinyl chloride), polyvinyl ethers (such aspolyvinyl methyl ether), polyvinylidene halides (such as polyvinylidenechloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose. Additional representative examples of polymersthat may be especially well suited for use in fabricating embodiments ofimplantable medical devices disclosed herein include ethylene vinylalcohol copolymer (commonly known by the generic name EVOH or by thetrade name EVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluoropropene) (e.g., SOLEF 21508, available from SolvaySolexis PVDF, Thorofare, N.J.), polyvinylidene fluoride (otherwise knownas KYNAR, available from ATOFINA Chemicals, Philadelphia, Pa.),ethylene-vinyl acetate copolymers, poly(vinyl acetate),styrene-isobutylene-styrene triblock copolymers, and polyethyleneglycol.

Method of Coating a Device

The coating described herein can be formed by spray coating or any othercoating process available in the art, such as dipping. Generally, thecoating involves dissolving or suspending the composition (e.g. polymerand drug), or one or more components thereof, in a solvent or solventmixture to form a solution, suspension, or dispersion of the compositionor one or more components thereof, applying the solution or suspensionto an implantable device, and removing the solvent or solvent mixture toform a coating or a layer of coating. Suspensions or dispersions of thecomposition described herein can be in the form of latex or emulsion ofmicroparticles having a size between 1 nanometer and 100 microns,preferably between 1 nanometer and 10 microns. Heat and/or pressuretreatment can be applied to any of the steps involved herein. Inaddition, if desirable, the coating described here can be subjected tofurther heat and/or pressure treatment. Some additional exemplaryprocesses of coating an implantable device that may be used aredescribed in, for example, Lambert T L, et al. Circulation, 1994, 90:1003-1011; Hwang C W, et al. Circulation, 2001; 104: 600-605; Van derGiessen W J, et al. Circulation, 1996; 94: 1690-1697; Lincoff A M, etal. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, J AmericanCollege Cardiology Meeting, Mar. 6, 2002, ACCIS2002, poster 1174-15;Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. ZKardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation 2003,107: 4, 559-64.

As used herein, the term “solvent” refers to a liquid substance orcomposition that is compatible with the polymer and is capable ofdissolving or suspending the polymeric composition or one or morecomponents thereof at a desired concentration. Representative examplesof solvents include chloroform, acetone, water (buffered saline),dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,)iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol,tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide(DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane,nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate,isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene,1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide,hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethylphosphoramide and a combination thereof.

Method of Use

In accordance with embodiments of the invention, a coating of thevarious described embodiments can be formed on an implantable device orprosthesis, e.g., a stent. For coatings including one or more activeagents, the agent will be retained on the medical device such as a stentduring delivery and expansion of the device, and released at a desiredrate and for a predetermined duration of time at the site ofimplantation. Preferably, the medical device is a stent. A stent havingthe above-described coating is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coating isparticularly useful for treating occluded regions of blood vesselscaused by abnormal or inappropriate migration and proliferation ofsmooth muscle cells, thrombosis, and restenosis. Stents may be placed ina wide array of blood vessels, both arteries and veins. Representativeexamples of sites include the iliac, renal, and coronary arteries.

For implantation of a stent, an angiogram is first performed todetermine the appropriate positioning for stent therapy. An angiogram istypically accomplished by injecting a radiopaque contrasting agentthrough a catheter inserted into an artery or vein as an x-ray is taken.A guidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein, and advanced into the appropriate blood vessel bysteering the catheter through the vascular system under fluoroscopicguidance. A stent having the above-described coating may then beexpanded at the desired area of treatment. A post-insertion angiogrammay also be utilized to confirm appropriate positioning.

The implantable device comprising a coating described herein can be usedto treat an animal having a condition or disorder that requires atreatment. Such an animal can be treated by, for example, implanting adevice described herein in the animal. Preferably, the animal is a humanbeing. Exemplary disorders or conditions that can be treated by themethod disclosed herein include, but not limited to, thrombosis, highcholesterol, hemorrhage, vascular dissection or perforation, vascularaneurysm, vulnerable plaque, chronic total occlusion, claudication,anastomotic proliferation for vein and artificial grafts, bile ductobstruction, ureter obstruction, tumor obstruction, restenosis andprogression of atherosclerosis in patient subsets including type Idiabetics, type II diabetics, metabolic syndrome and syndrome X,vulnerable lesions including those with thin-capped fibroatheromatouslesions, systemic infections including gingivitis, hellobacteria, andcytomegalovirus, and combinations thereof.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples. All parameters and data are not to beconstrued to unduly limit the scope of the embodiments of the invention.

Example 1 Porcine Implant Study

Described in this example is a 28 day porcine implant study thatcompared the 200 μg/cm² dose stent Lemans (a stent based on PVDF-co-HFP)with a clobetasol-only delivery stent, an everolimus-only stent, and aneverolimus-clobetasol combination drug delivery stent. The study wasperformed using three different drug delivery stents, Arm 1, Arm 2, andArm 3. Arm 1 is a Lemans stent that included 105 μg everolimus and usedas a control. Arm 2 was loaded with 185 μg clobetasol only, with noeverolimus. Arm 3 is loaded with 105 μg everolimus and 80 μg clobetasol.

The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretchmodel. Overstretch model refers to the technique of over-expanding theanimal arteries by up to 30% (using the stent and balloon) over theirnatural diameter so that the stent is more likely to cause injury andthus greater restenosis. This sometimes helps differentiate betweenefficacy of various stent systems.

Nine samples of each Arm stent were implanted, one for each coronaryartery. 24 hr release data in porcine serum were gathered. 3, 7 and 28day in vivo release data were gathered (from the mammary arteries), aswas 28 day quantitative coronary angioplasty (QCA), histology andmorphometry.

In this study, 12 mm Vision Small stents were used. All drug solutionswere sprayed in a 2% Solef™ in acetone/cyclohexanone formulation. Allstents had a 100 μg PBMA primer. Table 1 shows the coating design of thestents used in this study.

TABLE 1 Coating design Evererolimus Clobetasol Solid Drug (D) Polymer(P) D:P Drug % Target (μg) Target (μg) Target (μg) Arm 1 EverolimusSolef ™ 1:3 25.0 105 — 420 Arm 2 Clobetasol Solef ™ 1:4.2 19.2 — 185 962Arm 3 Ever & Clob Solef ™ 1:3.49 22.2 105 80 833

The release rate data are shown in Table 2. As can be seen from Table 2,a coating based on Solef™ is capable of simultaneous release of botheverolimus and clobetasol.

TABLE 2 Release rate data In vivo In vivo In vivo In vitro In vivo Invivo In vivo In vitro Day 3 Day 7 Day 28 24 hr Day 3 Day 7 Day 28 24 hr% % % % % % % % Clobetasol Clobetasol Clobetasol Clobetasol EverolimusEverolimus Everolimus Everolimus Release Release Release Release inRelease Release Release Release in Arm (n = 2) (n = 3) (n = 4) PS (n =3) (n = 2) (n = 3) (n = 4) PS (n = 3) 1 - Everolimus 37.6% 49.3% 66.7%30.0% 2 - Clobetasol 32.5% 43.1% 60.6% 26.7% 3 - Everolimus + 40.9%50.2% 71.9% 30.1% 35.1% 43.6% 60.4% 24.8% Clobetasol

The results of 28 day QCA are shown in FIG. 5, the 28 day histology dataare in FIG. 6, and the 28 day morphometry data are shown in FIG. 7 andsummarized in Table 3 below.

Neointimal Area is the total amount of neointima as measured by across-sectional vessel section. This is essentially the area inside theInternal Elastic Lamina (IEL) minus the total area of the vessel lumen.Neointima refers to the new intimal growth that forms after stentingwhich resides between the IEL and the vessel lumen. Neointimal Thicknessis the average distance between the IEL and the lumen. This isessentially the average thickness of the new intima that grows insidethe stent after stenting.

Injury Score is a standardized scoring system that scores the amount ofinjury created in the vessel by the stent implantation. Currently, weuse a range of 0 to 4 where 0 is no injury and 4 is the highest injury.There are specific quantitative and qualitative criteria for assigning agiven score to a vessel.

TABLE 3 28 Day morphometry data from FIG. 7 AVERAGE STANDARD DEVIATIONMedia Neointimal Media Neointimal Neointimal Area Neointimal % ThicknessInjury Area Area % Thickness Injury (mm{circumflex over ( )}2) Area(mm{circumflex over ( )}2) Stenosis (mm) Score (mm{circumflex over( )}2) (mm{circumflex over ( )}2) Stenosis (mm) Score Everolimus 1.211.81 27.83 0.28 1.83 Everolimus 0.23 0.72 13.18 0.11 0.23 Clobetasol1.09 1.73 24.86 0.29 1.79 Clobetasol 0.18 1.57 23.27 0.23 0.22Clobetasol/ 0.97 0.82 12.39 0.14 1.62 Clobetasol/ 0.18 0.39 7.54 0.040.29 Everolimus EverolimusThe p values from a t-test of the data from FIG. 7 are summarized inTable 4. A “t-test” returns the probability associated with a Student'st-Test that determines whether two samples are likely to have come fromthe same two underlying populations that have the same mean. The valuereturned from the test, “p”, is the probability that the two groups ofdata come from the same population. p Values less than or equal to 0.10or 0.05 are generally considered significant (Zar, J H. BiostatisticalAnalysis. Englewood Cliffs, N.J.: Prentice-Hall Inc, 1974. pp 101-108).

TABLE 4 p Values from a t-test of the data from FIG. 7 Media NeointimalNeointimal Injury Arm Comparison Area Area % Stenosis Thickness ScoreEVER COMBO 0.05 0.01 0.02 0.01 0.18 EVER CLOB 0.29 0.90 0.77 0.93 0.78COMBO CLOB 0.24 0.18 0.22 0.14 0.25

Example 2 Porcine Implant Study

Described in this example is a 28 day porcine implant study thatcompared an everolimus-only stent, an everolimus-clobetasol combinationdrug delivery stent, and a clobetasol-only stent. The drugs weredispersed in a Solef polymer matrix, available from Solvay Solexis PVDF,Thorofare, N.J. The study was performed using three different drugdelivery stents, Arm 1, Arm 2, and Arm 3. Arm 1 is Lemans stent (a stentbased on PVDF-co-HFP coating) that included 64 μg everolimus with adrug-polymer ratio of 1:4.9, which was used as a control. Arm 2 isloaded with 64 μg everolimus and 32 μg clobetasol with a drug-polymerratio of 1:4. Arm 3 was loaded with 32 μg clobetasol only with adrug-ratio of 1:4, with no everolimus. Table 5 shows the coating designof the stents used in this study.

The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretchmodel. Nine samples of each Arm stent were implanted, one for eachcoronary artery. 24 hr release data in porcine serum were gathered. 3, 7and 28 day in vivo release data were gathered (from the mammaryarteries), as was 28 day quantitative coronary angioplasty (QCA),histology and morphometry. 28 day QCA, histology, and morphometry werecollected from coronary arteries.

In this study, 12 mm Vision Small stents were used. All drug solutionswere sprayed in a 2% Solef™ in acetone/cyclohexanone formulation. Allstents had a 100 μg PBMA primer.

TABLE 5 Coating design Evererolimus Clobetasol Solid Drug (D) Polymer(P) D:P Drug % Target (μg) Target (μg) Target (μg) Arm 1 EverolimusSolef ™ 1:4.9 17.0 64 — 375 Arm 2 Ever & Clob Solef ™ 1:4 20.0 64 32 480Arm 3 Clobetasol Solef ™ 1:9 10.0 — 32 320

The release rate data are shown in Table 6. As can be seen from Table 6,a coating based on Solef™ is capable of simultaneous release of botheverolimus and clobetasol.

TABLE 6 Release rate data In Vitro In Vivo In Vivo In Vivo In Vivo InVitro In Vivo In Vivo In Vivo In Vivo 24 hr Day 1 Day 3 Day 7 Day 28 24hr Day 1 Day 3 Day 7 Day 28 % % % % % % % % % % Clobetasol ClobetasolClobetasol Clobetasol Clobetasol Everolimus Everolimus EverolimusEverolimus Everolimus Release in Release Release Release Release Releasein Release Release Release Release Arm PS (n = 3) (n = 4) (n = 4) (n =4) (n = 3) PS (n = 3) (n = 4) (n = 4) (n = 4) (n = 3) 1 - Everolimus

30.4% 33.1% 45.6% 62.2% 82.9% 2 - Everolimus + 35.1% 33.9% 45.8% 55.4%81.2% 28.4% 31.9% 40.0% 48.3% 71.1% Clobetasol 3 - Clobetasol 34.2%33.9% 48.0% 60.5% 85.0%

The results of the 28 day morphometry data are shown in FIG. 8 andsummarized in Table 7 below.

TABLE 7 28 Day morphometry data from FIG. 8 AVERAGE STANDARD DEVIATIONMedia Neointimal Neointimal Media Neointimal Neointimal Area Area %Thickness Injury Area Area % Thickness Injury (mm{circumflex over ( )}2)(mm{circumflex over ( )}2) Stenosis (mm) Score (mm{circumflex over( )}2) (mm{circumflex over ( )}2) Stenosis (mm) Score Ever 64 ug 1.222.30 30.38 0.34 1.64 0.26 2.06 25.32 0.33 0.59 Ev/Cl 64/32 ug 0.92 1.1014.99 0.23 1.07 0.26 0.34 4.93 0.19 0.29 Clob 32 ug 1.21 3.26 43.04 0.461.47 0.12 1.54 22.13 0.23 0.30The p values from a t-test of the data from FIG. 8 are summarized inTable 8.

TABLE 8 p Values from a t-test of the data from FIG. 8 NeointimalNeointimal Area Thickness Injury Arm Comparison (mm²) % Stenosis (mm)Score Ever Combo 0.15 0.13 0.41 0.03 Ever Clob 0.36 0.37 0.46 0.49 ComboClob 0.03 0.05 0.09 0.04

Clobetasol is non-toxic even at the highest concentrations typicallytested in cell culture (10 ⁻⁶ M). FIG. 9 depicts a proliferation assaythat shows a dose dependent inhibition of vascular smooth muscleproliferation and a low EC50 value of 3×10⁻¹¹ M. The Efficacy of thedrug is 25%.

A proliferation assay is a cell culture assay in which smooth musclecells are exposed to various concentrations of a given drug. The y-axisis a measure of the total number of DNA strands or cell nuclei. If cellsare dividing (proliferating), the amount of DNA increases. EC50 is theconcentration of drug that causes half the total effect. For example, ifthe greatest amount of proliferation reduction is 60% reduction ascompared to no drug, then the EC50 is the concentration of drug thatcauses a 30% reduction in proliferation. Efficacy refers to theeffectiveness of the drug in preventing proliferation of smooth musclecells.

FIG. 10 depicts a proliferation assay with everolimus only, which alsoshows inhibition of vascular smooth muscle proliferation. The efficacyof the drug is 62%.

FIG. 11 depicts results of a proliferation assay with varying ratios ofeverolimus and clobetasol. FIG. 11 illustrates a plot of the efficacy ofinhibition of vascular smooth muscle proliferation versus the logarithmof the everolimus-clobetasol ratio. The circled portion of the curve inFIG. 11 shows that everolimus and clobetasol have a synergistic effectthat results in a higher efficacy within a range of the ratio of the twodrugs.

Example 3

The results of additional preclinical dosing studies (porcine 10%safety) are presented to demonstrate the continued efficacy in reducingneointimal proliferation and inflammation at both 28 and 90 days, whileachieving appropriate vascular healing (as assessed by vascularre-endothelialization).

Two safety studies, one 28-day and one 90-day were designed to includethree arms: 100 μg everolimus alone; 100 μg everolimus: 10 μg clobetasol(100:10) and 100 μg everolimus: 1 μg clobetasol (100:1).

The 28-day study showed a 32.7±12.0% in-stent stenosis rate ineverolimus arm, 17.9±5.0% in the 100:10 arm, and 16.9±5.9% in the 100:1arm. In the 90-day study, the in-stent stenosis rates were 45.2±21.5%,14.2±7.9% and 16.1±8.6% in the everolimus 100, 100:10 and 100:1,respectively. The data show that both doses of combination drugsignificantly (p<0.05) reduced % stenosis versus everolimus 100 at both28 and 90 days post implant.

Evaluation via light microscopy and SEM at 28 days revealed that lowdose (100:1) had near complete re-endothelialization, which wascomparable to everolimus alone. Furthermore, histopathologicalevaluation at 90 days demonstrated that both drug combination armsmaintained vascular healing with reduced stenosis and inflammation, ascompared to everolimus alone. In conclusion, 100:1 arm appears to bevery effective in reducing and maintaining reduced vascular stenosiswhile also showing a good safety profile at 28 and 90 days in theporcine safety (10%) coronary arterial model.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

What is claimed is:
 1. A drug-delivery system, comprising: at least 100μg of everolimus; and clobetasol, such that the amount of everolimus byweight is at least 10 times more than clobetasol.
 2. The drug-deliverysystem of claim 1, wherein the system is a stent.
 3. The drug-deliverysystem of claim
 1. where the system is a polymeric coated stent, suchthat the everolimus and clobetasol are in the polymeric coating.
 4. Thedrug-delivery system of claim 3, wherein the coating includes 2 layersor regions such that the everolimus is in one layer or region and theclobetasol is in another layer or region.
 5. The drug-delivery system ofclaim 1, wherein the drugs are released in sequence.
 6. Thedrug-delivery system of claim 1, wherein the drugs are releasedsimultaneously.
 7. The drug-delivery system of claim 1, wherein the drugrelease profile includes at least a period of overlapping orsimultaneous release profile of the everolimus and clobetasol.
 8. Thedrug-delivery system of claim 1, wherein the ratio of the everolimus tothe clobetasol is 10:1 to 100:1 (w/w).
 9. A stent, comprising: aradially expandable body; and a combination of (a) a first drug selectedfrom a group consisting of rapamycin, Biolimus A9, deforolimus, AP23572,tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578),40-O-(2-hydroxy)ethylrapamycin, 40-O-(3-hydroxy)propylrapamycin,40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and40-epi-(N1-tetrazoly)prapamycin, and (b) a second drug consisting ofclobetasol, carried by the stent, wherein the minimum amount of thefirst drug carried by the stent is 100 μg, and wherein the ratio of thefirst drug to the second drug is 10:1 to 100:1 (w/w).
 10. The stent ofclaim 9, wherein the stent includes a coating carrying the first andsecond drugs.
 11. The stent of claim 10, wherein the coating includes atleast two layers such that the first drug is in one layer and the seconddrug is on another layer.
 12. The stent of claim 9, wherein the stent isa bioabsorbable stent.
 13. The stent of claim 12, wherein at least oneof the drugs is in the body of the bioabsorbable stent and at least oneof the drugs is in a coating on the bioabsorbable stent.